Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity

Dixon, Christine L., Harrison, Neil L., Lynch, Joseph W. and Keramidas, Angelo (2015) Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity. British Journal of Pharmacology, 172 14: 3522-3536. doi:10.1111/bph.13142

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Author Dixon, Christine L.
Harrison, Neil L.
Lynch, Joseph W.
Keramidas, Angelo
Title Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity
Formatted title
Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
Publication date 2015
Sub-type Article (original research)
DOI 10.1111/bph.13142
Open Access Status
Volume 172
Issue 14
Start page 3522
End page 3536
Total pages 15
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley and Sons
Collection year 2016
Language eng
Formatted abstract
Background and Purpose: GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors.

Experimental Approach: We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism.

Key Results: At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening.

Conclusions and Implications: As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines.
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Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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